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Although lack of EGFR signalling primarily affects skin and brain development and tissue homeostasis, aberrant EGFR activation through overexpression or mutation converts the receptor into a potent oncogenic driver. This occurs particularly in human cancers such as glioblastoma, non\u2013small-cell lung carcinoma, colorectal cancer, hepatocellular carcinoma, pancreatic ductal adenocarcinoma and head and neck squamous cell carcinoma. Genetically engineered mouse models have been instrumental in advancing our understanding of EGFR biology by elucidating mechanisms of disease initiation and progression, and by enabling the preclinical evaluation of novel therapeutic strategies. The ability to manipulate EGFR expression and activity in a spatiotemporally controlled manner in mice has allowed us to dissect its complex signalling pathways and their downstream effects, revealing unexpected functions of EGFR and enhancing its relevance for translational research. In this paper, we focus on the context-specific roles of EGFR during tumourigenesis, the therapeutic relevance of EGFR inhibition in cancer and the molecular mechanisms underlying skin toxicities associated with EGFR-targeted therapies.<\/jats:p>\n                  <jats:p>This article is part of the discussion meeting issue \u2018Epidermal growth factor receptor after 40 years\u2019.<\/jats:p>","DOI":"10.1098\/rstb.2024.0497","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T07:08:53Z","timestamp":1787814533000},"source":"Crossref","is-referenced-by-count":1,"title":["Functions of the EGFR in health and disease"],"prefix":"10.1098","volume":"381","author":[{"given":"Thomas","family":"Bauer","sequence":"first","affiliation":[{"name":"Center for Cancer Research, Medical University of Vienna , Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Holcmann","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Medical University of Vienna , Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6129-5613","authenticated-orcid":false,"given":"Maria","family":"Sibilia","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, Medical University of Vienna , Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"175","published-online":{"date-parts":[[2026,8,27]]},"reference":[{"key":"2026082703084726400_RSTB20240497C1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1038\/376337a0","article-title":"Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor","volume":"376","author":"Miettinen","year":"1995","journal-title":"Nature"},{"key":"2026082703084726400_RSTB20240497C2","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1126\/science.7618084","article-title":"Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype","volume":"269","author":"Threadgill","year":"1995","journal-title":"Science"},{"key":"2026082703084726400_RSTB20240497C3","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1126\/science.7618085","article-title":"Strain-dependent epithelial defects in mice lacking the EGF receptor","volume":"269","author":"Sibilia","year":"1995","journal-title":"Science"},{"key":"2026082703084726400_RSTB20240497C4","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1006\/dbio.1997.8593","article-title":"Impaired lung branching morphogenesis in the absence of functional EGF receptor","volume":"186","author":"Miettinen","year":"1997","journal-title":"Dev. 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